Systemic AR-C155858 During Fixed Treadmill Exercise in MPTP Mice: An Exploratory Study

Abstract

Treadmill exercise improves motor and dopaminergic phenotypes in toxin-based Parkinson’s disease models, but the contribution of monocarboxylate transport remains uncertain. This small-scale, hypothesis-generating exploratory study tested whether systemic AR-C155858, an MCT1/MCT2 inhibitor used in experimental systems, altered lactate kinetics and recovery-related outcomes in MPTP-treated mice during identical treadmill exercise. Its purpose was to detect a coordinated phenotype that could justify subsequent confirmatory mechanistic testing. The two-group design was not intended to estimate the independent effect of exercise, the effect of AR-C155858 without exercise, or a drug-by-exercise interaction. Male C57BL/6J mice received MPTP (20 mg/kg/day, intraperitoneally, 5 days) and, after 3 days, completed 4 weeks of forced treadmill exercise (16 m/min, 40 min/day, 5 days/week, 5° incline). Mice received vehicle (Ex-Veh) or AR-C155858 (Ex-AR; 10 mg/kg intraperitoneally, 30 min before exercise). Blood lactate was measured in weeks 1 and 4; motor behavior was assessed before MPTP, after MPTP, and after the intervention; endpoint striatal TH, Iba1, GFAP, and dopamine metabolites were measured. AR-C155858 was associated with higher 30-min post-exercise lactate and smaller recovery amplitude, but not altered lactate peak increment or AUC. Ex-AR mice showed smaller changes in open-field distance, pole-test turning, stride length, and fore-hind overlap, together with lower endpoint striatal TH and dopamine and higher Iba1. GFAP and DOPAC did not differ significantly; HVA was not tested because multiple values were below quantification. In male MPTP-treated mice under a common treadmill condition, systemic AR-C155858 was associated with delayed peripheral lactate decline and less favorable motor and endpoint striatal outcomes. Because MCT1/MCT2 expression, localization, and target engagement were not measured, the findings do not establish a brain- or cell-specific MCT mechanism. These findings generate testable hypotheses for a subsequent, larger factorial mechanistic study. Animal-level open-field data, a baseline-adjusted sensitivity analysis, and executable analysis code are supplied as Supplementary materials.